The present invention relates to novel compounds, and therapeutically acceptable salts thereof, which inhibit exogenously or endogenously stimulated gastric acid secretion and thus can be used in the prevention and treatment of gastrointestinal inflammatory diseases. In further aspects, the invention relates to compounds of the invention for use in therapy; to processes for preparation of such new compounds; to pharmaceutical compositions containing at least one compound of the invention, or a therapeutically acceptable salt thereof, as active ingredient; and to the use of the active compounds in the manufacture of medicaments for the medical use indicated above.
Substituted imidazo[1,2-a]pyridines, useful in the treatment of peptic ulcer diseases, are known in the art, e.g. from EP-B-0033094 and U.S. Pat. No. 4,450,164 (Schering Corporation); from EP-B-0204285 and U.S. Pat. No. 4,725,601 (Fujisawa Pharmaceutical Co.); from WO 9418199 and WO 9510518 (Byk Gulden Lomberg Chem.) and from publications by J. J. Kaminski et al. in the Journal of Medical Chemistry (vol. 28, 876-892, 1985; vol. 30, 2031-2046, 1987; vol. 30, 2047-2051, 1987; vol. 32, 1686-1700, 1989; and vol. 34, 533-541, 1991).
For a review of the pharmacology of the gastric acid pump (the H+, K+-ATPase), see Sachs et al. (1995) Annu. Rev. Pharmacol. Toxicol. 35: 277-305.
It has surprisingly been found that compounds of the Formula I, which are substituted imidazopyridine derivatives, are effective as inhibitors of the gastrointestinal H+, K+-ATPase and thereby as inhibitors of gastric acid secretion.
In one aspect, the invention thus relates to compounds of the general Formula I: 
or a pharmaceutically acceptable salt thereof, wherein
R1 is
(a) H,
(b) C1-C6 alkyl,
(c) C1-C6 alkenyl,
(d) CH2OH,
(e) halogen, or
(f) thiocyano
R2 is
(a) C1-C6 alkyl,
(b) hydroxyalkyl,
(c) C1-C6 alkoxy C1-C6 alkyl,
(d) hydroxy C1-C6 alkoxy C1-C6 alkyl,
(e) C1-C6 alkylthio C1-C6 alkyl,
(f) cyano C1-C6 alkyl,
(g) halogenated C1-C6 alkyl, or
(h) aminocarbonyl C1-C6 alkyl
R3 is
(a) H,
(b) C1-C6 alkoxy,
(c) C1-C6 alkyl,
(d) halogen,
(e) hydroxy C1-C6 alkyl.
(f) hydroxy C1-C6 alkoxy,
(g) C1-C6 alkoxy C1-C6 alkyl,
(h) C1-C6 alkoxy C1-C6 alkoxy,
(i) C1-C6 alkoxycarbonyl,
(j) C1-C6 alkanoyl,
(k) halogenated C1-C6 alkyl,
(l) NO2,
(m) CN,
(n) C1-C6 sulfonyl,
(o) C1-C6 sulfinyl,
(p) C1-C6 alkylthio,
(q) C1-C6 alkylaminosulfonyl,
(r) C1-C6 (alkyl)2aminosulfonyl,
(s) aminosulfonyl,
(t) C1-C6 alkylsulfonylamino,
(u) C1-C6 (alkylsulfonyl)2amino,
(v) trifluoromethylsulfonylamino,
(x) C1-C6 alkylcarbonylamino,
(y) C1-C6 alkoxycarbonylamino, or
(Z) C1-C6 aminocarbonylamino, optionally substituted by one or two C1-C6 alkyl groups,
R4 is
(a) H,
(b) C1-C6 alkyl,
(c) halogenated C1-C6 alkyl,
(d) C1-C6 alkoxy, or
(e) halogen.
Ar is a phenyl, thienyl, furanyl, naphthyl, or pyridyl group substituted with one or more substituents selected from the group consisting of R5, R6, and R7.
X is 
R5 is
(a) H,
(b) C1-C6 alkyl,
(c) C1-C6 alkoxy,
(d) hydroxy,
(e) hydroxy C1-C6 alkyl,
(f) hydroxy C1-C6 alkoxy,
(g) halogenated C1-C6 alkyl,
(h) halogenated C1-C6 alkoxy,
(i) C1-C6 alkoxy C1-C6 alkyl,
() halogen,
(k) hydroxy C1-C6 alkoxy C1-C6 alkyl,
(l) CN,
(m) C1-C6 alkoxycarbonyl,
(n) C1-C6 alkoxycarbonyloxy,
(O) C1-C6 alkylsulfonyloxy,
(p) trifluoromethylsulfonyloxy,
(q) C1-C6 acyloxy C1-C6 alkyl,
(r) C1-C6 alkylsulfonyl C1-C6 alkyl.
(s) C1-C6 alkylsulfinyl C1-C6 alkyl,
(t) C1-C6 alkylthio C1-C6 alkyl,
(u) C1-C6 alkoxycarbonylamino C1-C6 alkyl,
(v) aryl,
(x) amino C1-C6 alkyl,
(y) NHCxe2x95x90OR12 
(z) H or C1-C4 alkyl substituted 
xe2x80x83-group
(aa) H or C1-C4 alkyl substituted 
xe2x80x83-group, or
(ab) C1-C6 alkyl sulfonyl amino
R6 is
(a) H,
(b) C1-C6 alkyl,
(c) halogen,
(d) hydroxy C1-C6 alkyl,
(e) halogenated C1-C6 alkyl,
(f) halogenated C1-C6 alkoxy,
(e) C1-C6 alkoxy C1-C6 alkyl, or
(f) CN
R7 is
(a) H,
(b) C1-C6 alkyl,
(c) C1-C6 alkoxy,
(d) halogen,
(e) NO2,
(f) halogenated C1-C6 alkyl,
(g) halogenated C1-C6 alkoxy,
(h) aryloxy, or
(i) CN
R8 is
(a) H or
(b) C1-C6 alkyl R12 is
(a) C1-C6 alkoxy,
(b) C1-C6 alkoxy C1-C4 alkoxy,
(c) NH2,
(d) hydroxy C2-C4 alkoxy,
(e) C1-C6 alkyl carbonyloxy C2-C4 alkoxy,
(f) halogenated C2-C4 alkoxy,
(g) halogenated C1-C4 alkyl,
(h) hydroxy C1-C4 alkyl,
(i) C1-C6 alkyl carbonyloxy C1-C4 alkyl,
(j) aryl,
(k) aryl C1-C4 alkyl,
(l) C1-C4 sulfanyl C2-C4 alkoxy,
(m) C1-C4 sulfinyl C2-C4 alkoxy, or
(n) C1-C4 sulfonyl C2-C4 alkoxy,
R5 and R6 are in the ortho positions relative to X
R7 is in the meta or para position relative to X
R5 and R8 may together form a hydroxy- or alkoxy-substituted 5- or 6-membered ring,
provided that one of R3 and R4xe2x89xa0H or halogen
provided also that at least one of R5, R6 and R7xe2x89xa0H
provided also that when R5=(y),(z),(aa) or (ab), at least one of R3 and R4xe2x89xa0H
provided also that when R1=H or Cl, XArxe2x89xa0OCH2Ar
provided also that when R1=H, halogen or CH2OH, at least one of R5 and R6 is C1-C6 alkyl
provided also that when R2 is CH2OH or CH2CN, at least one of R5 and R6 is C1-C6 alkyl
The term xe2x80x9carylxe2x80x9d includes phenyl, naphthyl, thienyl, furyl, pyridyl or imidazolyl, optionally substituents by 1-3 substituents selected from H, C1-C6 alkyl, C1-C6 alkoxy, halogen or CF3.
As used herein, the term xe2x80x9cC1-C6 alkylxe2x80x9d denotes a straight or branched alkyl group having from 1 to 6 carbon atoms. Examples of C1-C6 alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and hexyl.
The term xe2x80x9chalogenxe2x80x9d includes fluoro, chloro, bromo and iodo.
The term xe2x80x9cpyridylxe2x80x9d includes the 2-, 3-, and 4-isomers and the terms thienyl and furanyl include the 2-, and 3-isomers.
Both the pure enantiomers, racemic mixtures and unequal mixtures of the two enantiomers are within the scope of the invention. It should be understood that all the possible diastereomeric forms (pure enantiomers, racemic mixtures and unequal mixtures of two enantiomers) are within the scope of the present invention. Also included in the invention are derivatives of the compounds of the Formula I which have the biological function of the compounds of the Formula I.
Depending on the process conditions the end products of the Formula I are obtained either in neutral or salt form. Both the free base and the salts of these end products are within the scope of the present invention.
Acid addition salts of the new compounds may in a manner known per se be transformed into the free base using basic agents such as alkali or by ion exchange. The free base obtained may also form salts with organic or inorganic acids.
In the preparation of acid addition salts, preferably such acids are used which form suitable therapeutically acceptable salts. Examples of such acids are hydrohalogen acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, pyruvic acid, p-hydroxybensoic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, halogenbensenesulfonic acid, toluenesulfonic acid or naphthalenesulfonic acid.
Preferred compounds according to the invention are those of the formula I wherein
R1 is H, CH3, CH2OH;
R2 is CH3, CH2CH3, CH2CH2OH, CH2CH2SCH3, CH2CH2OCH3 or CH2CH2CN;
R3 is H, CH3, CH2CH3, F, Cl, Br, OCH3,OCH2CH3, CH2OH, CH2CH2OH, OCH2CH2OH, CH2CH2OCH3, OCH2CH2OCH3, Cxe2x95x90OOCH3, Cxe2x95x90OOCH2CH3 Cxe2x95x90OCH3, Cxe2x95x90OCH2CH3, Cxe2x95x90OCH(CH3)2, or Cxe2x95x90OCH2CH2CH3,
R4is H, CH3, CH2CH3, F, Cl, Br, OCH3 or OCH2CH3;
Ar is phenyl, thienyl, furyl naphthyl; 
R5is H, CH3, CH2CH3, OCH3, OH, CH2OH, CH2OCH3, CH2CH2OH, CH2CH2OCH3, OCH2CH2OH, OCxe2x95x90OOCH3, OCxe2x95x90OCH2CH3, OCHF2, OCF3, F, Cl, Br, CN, phenyl, CH2CH2OCxe2x95x90OCH3, CH2NHCxe2x95x90OOCH3 or CH2NHCxe2x95x90OOCH2CH3;
R6 is H, CH3, CH2CH3, CF3, OCF3, OCF2H, F, Cl, Br, or CH2OCH3;
R7 is H, F, Cl Br, OCF2H, or OCF3;
R8 is H or CH3, or CH2CH3.
More preferred compounds according to the invention are those of the formula I wherein
R1 is H, CH3 or CH2OH;
R2 is CH3, CH2CH3, CH2OH, CH2SCH3, CH2OCH3 or CH2CN;
R3 is H, CH3, CH2CH3, OCH3, OCH3, CH2OH, Cxe2x95x90OCH2CH; Cxe2x95x90OOCH2CH3, Cxe2x95x90OCH3, Cxe2x95x90OCH2CH3, or Cxe2x95x90OCH2CH2CH3;
R4 is H, or CH3;
Ar is phenyl, thienyl or furyl
X is 
R5 is H, CH3, CH2CH3, OCH3, OH, CH2OH, CH2OCH3, CH2CH2OH, CH2CH2OCH3, OCH2CH2OH, OCxe2x95x90OOCH3, OCxe2x95x90OCH2CH3, OCHF2, OCF3, F, Cl, Br, CN, CH2CH2OCxe2x95x90OCH3, CH2NHCxe2x95x90OOCH3 or CH2NHCxe2x95x90OOCH2CH3 
R6 is H, CH3, CH2CH3, CF3, OCF3, OCF2H, F, Cl, Br or CH2OCH3;
R7 is H, F, Cl, Br, OCF2H, OCF3;
R8 is H or CH3.
Preparation
The present invention also provides the following processes A, B, C, D or E for the manufacture of compounds with the general Formula I.
Process A
Process A for manufacture of compounds with the general Formula I comprises the following steps:
Compounds of the general Formula II 
wherein X1 is NH2 or OH, and R1, R2, R3, and R4 are as defined for Formula I, can be reacted with compounds of the general Formula III 
wherein xe2x80x9cArxe2x80x9d is as defined for Formula I and Y is a leaving group, such as a halide, tosyloxy or mesyloxy, to the compounds of the Formula I.
It is convenient to conduct this reaction in an inert solvent, e.g. acetone, acetonitrile, dimethoxyethane, methanol, ethanol or dimethylformamide with or without a base. The base is e.g. an alkali metal hydroxide, such as sodium hydroxide and potassium hydroxide; an alkali metal carbonate, such as potassium carbonate and sodium carbonate; or an organic amine, such as triethylamine
Process B
Process B for manufacture of compounds with the general Formula I, wherein X is NH, comprises the following steps:
Compounds of the general Formula IV 
wherein R1 , R2, R3 and R4 are as defined for Formula I, can be reacted with compounds of the general Formula V 
wherein xe2x80x9cArxe2x80x9d are as defined for Formula I, in the presence of a Lewis acid e.g. zinc chloride to the compounds of the Formula VI 
wherein R1, R2, R3, R4 and Ar are as defined for Formula I, whereupon the compounds of the general Formula VI are reduced e.g. by using sodium borohydride or sodiumcyano borohydride to compounds of the general Formula I, wherein X is NH. The reactions can be carried out under standard conditions in an inert solvent e.g. methanol or ethanol.
Process C
Process C for manufacture of compounds with the general Formula I, wherein R1 is CH2OH or H comprises the following steps:
Compounds of the general Formula VII 
wherein X1 is NH2 or OH, and R2, R3 and R4 are as defined for Formula I, can be reacted with compounds of the general Formula III 
wherein Ar is as defined for Formula I and Y is a leaving group, such as a halide, tosyloxy or mesyloxy, to the compounds of the Formula VIII 
wherein R2, R3, R4, Ar and X are as defined for Formula I.
It is convenient to conduct this reaction in an inert solvent, e.g. acetone, acetonitrile, dimethoxyethane, methanol, ethanol or N,N-dimethylformamide with or without a base. The base is e.g. an alkali metal hydroxide, such as sodium hydroxide and potassium hydroxide; an alkali metal carbonate, such as potassium carbonate and sodium carbonate, or an organic amine, such as triethylamine.
Reduction of compounds of the general Formula VIII, e.g. by using lithium aluminum hydride in tetrahydrofuran or ether yields the compounds of the general Formula I wherein R1 is CH2OH.
Hydrolysis of compounds of formula VIII, e.g. by using a base such as sodium hydroxide or an acid such as hydrochloric acid. After hydrolysis, decarboxylation in an inert solvent such as diphenylether gives the compounds of formula I wherein R1 is H.
Process D
Process D for manufacture of compounds with the general Formula I, wherein R1 is H or CH2OH and X is NH comprises the following steps:
Compounds of the Formula IX 
R2, R3, and R4 are as defined for Formula I, can be reacted with compounds of the general Formula V 
wherein Ar is as defined for Formula I, in the presence of a Lewis acid, e.g. zinc chloride to the compounds of the Formula X 
wherein R2, R3, R4 and Ar are as defined for Formula I, whereupon the compounds of the general Formula X are reduced, e.g. by using sodium borohydride or sodium cyano borohydride to compounds of the general Formula XI 
wherein R2, R3, R4 and Ar are as defined for Formula I. The reactions can be carried out under standard conditions in an inert solvent e.g. methanol or ethanol.
Reduction of compounds of the general Formula XI e.g. by using lithium aluminium hydride in tetrahydrofuran or ether yields the compounds of the general Formula I wherein R1 is CH2OH and X is NH.
Hydrolysis of compounds of formula XI, e.g. by using a base such as sodium hydroxide or an acid such as hydrochloric acid. After hydrolysis, decarboxylation in an inert solvent such as diphenylether gives the compounds of formula I wherein R1 is H.
Process E
Condensation of compounds of the general Formula XII 
wherein R3, R4, and Ar are as defined for Formula I, with (xcex1-halocarbonyl intermediates of the general formula R2COCH(Z)R1 wherein Z is a leaving group such as Br or Cl, in an inert solvent e.g. acetonitrile or ethanol results in formation of compounds of the general Formula XIII wherein R2, R3, R4, and Ar are as defined for Formula I 
Medical Use
In a further aspect, the invention relates to compounds of the formula I for use in therapy, in particular for use against gastrointestinal inflammatory diseases. The invention also provides the use of a compound of the formula I in the manufacture of a medicament for the inhibition of gastric acid secretion, or for the treatment of gastrointestinal inflammatory diseases.
The compounds according to the invention may thus be used for prevention and treatment of gastrointestinal inflammatory diseases, and gastric acid-related diseases in mammals including man, such as gastritis, gastric ulcer, duodenal ulcer, reflux esophagitis and Zollinger-Ellison syndrome. Furthermore, the compounds may be used for treatment of other gastrointestinal disorders where gastric antisecretory effect is desirable, e.g. in patients with gastrinomas, and in patients with acute upper gastrointestinal bleeding. They may also be used in patients in intensive care situations, and pre-and postoperatively to prevent acid aspiration and stress ulceration.
The typical daily dose of the active substance varies within a wide range and will depend on various factors such as for example the individual requirement of each patient, the route of administration and the disease. In general, oral and parenteral dosages will be in the range of 5 to 1000 mg per day of active substance.
Pharmaceutical Formulations
In yet a further aspect, the invention relates to pharmaceutical compositions containing at least one compound of the invention, or a therapeutically acceptable salt thereof, as active ingredient.
The compounds of the invention can also be used in formulations together with other active ingredients, e.g. antibiotics, such as amoxicillin.
For clinical use, the compounds of the invention are formulated into pharmaceutical formulations for oral, rectal, parenteral or other mode of administration. The pharmaceutical formulation contains a compound of the invention in combination with one or more pharmaceutically acceptable ingredients. The carrier may be in the form of a solid, semi-solid or liquid diluent, or a capsule. These pharmaceutical preparations are a further object of the invention. Usually the amount of active compounds is between 0.1-95% by weight of the preparation, preferably between 0.1-20% by weight in preparations for parenteral use and preferably between 0.1 and 50% by weight in preparations for oral administration.
In the preparation of pharmaceutical formulations containing a compound of the present invention in the form of dosage units for oral administration the compound selected may be mixed with solid, powdered ingredients, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture is then processed into granules or pressed into tablets.
Soft gelatin capsules may be prepared with capsules containing a mixture of the active compound or compounds of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatin capsules. Hard gelatin capsules may contain granules of the active compound. Hard gelatin capsules may also contain the active compound in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin.
Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the active substance mixed with a neutral fat base; (ii) in the form of a gelatin rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatin rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions containing from 0.1% to 20% by weight of the active ingredient and the remainder consisting of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain coloring agents, flavoring agents, saccharine and carboxymethyl cellulose or other thickening agent. Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.
Solutions for parenteral administration may be prepared as a solution of a compound of the invention in a pharmaceutically acceptable solvent, preferably in a concentration from 0.1% to 10% by weight. These solutions may also contain stabilizing ingredients and/or buffering ingredients and are dispensed into unit doses in the form of ampoules or vials. Solutions for parenteral administration may also be prepared as a dry preparation to be reconstituted with a suitable solvent extemporaneously before use.
The compounds according to the invention can also be used in formulations together with other active ingredients, e.g. for the treatment or prophylaxis of conditions involving infection by Helicobacter pylori of human gastric mucosa. Such other active ingredients may be antimicrobial agents, in particular:
xcex2-lactam antibiotics such as amoxicillin, ampicillin, cephalothin, cefaclor or cefixime;
macrolides such as erythromycin, or clarithromycin,
tetracyclines such as tetracycline or doxycycline;
aminoglycosides such as gentamycin, kanamycin or amikacin;
quinolones such as norfloxacin, ciprofloxacin or enoxacin;
others such as metronidazole, nitrofurantoin or chloramphenicol; or
preparations containing bismuth salts such as bismuth subcitrate, bismuth subsalicylate, bismuth subcarbonate, bismuth subnitrate or bismuth subgallate.
Examples